Method for synthesizing pirfenidone

ABSTRACT

A process for synthesizing pirfenidone from bromobenzene having less than about 0.15% by weight dibromobenze is disclosed. Also disclosed are processes of synthesizing pirfenidone without using ethyl acetate or n-butanol, and pirfenidone having controlled levels of ethyl acetate, n-butanol, di(5-methyl-2-pyridinone)benzenes, and other impurities having specified retention times. Also disclosed are formulated dosage forms including the disclosed pirfenidone.

CROSS REFERENCE TO RELATED APPLICATIONS

This is a continuation of U.S. patent application Ser. No. 12/792,387,filed Jun. 2, 2010, which in turn claims priority to U.S. ProvisionalApplication No. 61/183,588, filed Jun. 3, 2009, the entire disclosuresof which are each incorporated herein by reference.

BACKGROUND

1. Field of the Disclosure

This disclosure relates generally to methods for synthesizingpirfenidone. More specifically, this disclosure relates to a process forpreparing pirfenidone using a bromobenzene reagent having less thanabout 0.15% by weight dibromobenzene and using copper(I) oxide as acatalyst, instead of a copper (I) or (II) halide.

2. Brief Description of the Related Art

Pirfenidone is a non-peptide synthetic molecule with a molecular weightof 185.23 daltons. Its chemical elements are expressed as C₁₂H₁₁NO, andits structure is known. The synthesis of pirfenidone has been workedout. Pirfenidone is manufactured and being evaluated clinically as abroad-spectrum anti-fibrotic drug. Pirfenidone has anti-fibroticproperties via: decreased TNF-α expression, decreased PDGF expression,and decreased collagen expression. Several pirfenidone InvestigationalNew Drug Applications (INDs) are currently on file with the U.S. Foodand Drug Administration. Phase II human investigations have beeninitiated or completed for pulmonary fibrosis, renal glomerulosclerosis,and liver cirrhosis. There have been other Phase II studies that usedpirfenidone to treat benign prostate hypertrophy, hypertrophic scarring(keloids), and rheumatoid arthritis.

One important use of pirfenidone is known to be providing therapeuticbenefits to patients suffering from fibrosis conditions such asHermansky-Pudlak Syndrome (HPS) associated pulmonary fibrosis andidiopathic pulmonary fibrosis (IPF). Pirfenidone demonstrates apharmacologic ability to prevent or remove excessive scar tissue foundin fibrosis associated with injured tissues including that of lungs,skin, joints, kidneys, prostate glands, and livers. Published andunpublished basic and clinical research suggests that pirfenidone maysafely slow or inhibit the progressive enlargement of fibrotic lesions,remove pre-existing fibrotic lesions, and prevent formation of newfibrotic lesions following tissue injuries.

It is understood that one mechanism by which pirfenidone exerts itstherapeutic effects is by modulating cytokine actions. Pirfenidone is apotent inhibitor of fibrogenic cytokines and TNF-α. It is welldocumented that pirfenidone inhibits excessive biosynthesis or releaseof various fibrogenic cytokines such as TGF-β1, bFGF, PDGF, and EGF.Zhang S et al., Australian New Eng. J. Ophthal., 26:S74-S76 (1998).Experimental reports also show that pirfenidone blocks the synthesis andrelease of excessive amounts of TNF-α from macrophages and other cells.Cain et al., Int. J. Immunopharm., 20:685-695 (1998).

Pirfenidone has been studied in clinical trials for use in treatment ofIPF. Thus, there is a need for a synthetic scheme that providespirfenidone having sufficient purity as an active pharmaceuticalingredient (API) and involves efficient and economical processes. Priorbatches of pirfenidone were shown to have residual solvent traces ofethyl acetate (e.g., about 2 ppm) and butanol.

SUMMARY

Disclosed herein are methods of preparing pirfenidone. Morespecifically, disclosed herein is a method of synthesizing pirfenidonecomprising admixing bromobenzene, 5-methyl-2-pyridone, cuprous oxide,and an organic solvent under conditions sufficient to form pirfenidone,wherein the bromobenzene comprises less than about 0.15% by weightdibromobenzene. The admixing can be performed under elevatedtemperatures, for example at least about 100° C. The organic solvent cancomprise dimethyl formamide.

In some embodiments, the method further comprises washing thepirfenidone with a saline solution. The saline solution can compriseabout 10 wt % to about 15 wt % sodium chloride. In various embodiments,the method further comprises extracting the pirfenidone with anextracting solvent. The extracting solvent can comprise toluene.

In various embodiments, the method further comprises admixing a basewith the bromobenzene, 5-methyl-2-pyridone, cuprous oxide, and organicsolvent. The base can be an inorganic base. In a specific embodiment,the inorganic base comprises a carbonate, and more specifically,potassium carbonate.

In some embodiments, the method further comprises crystallizing thepirfenidone from a solvent mixture comprising heptanes and toluene toform purified pirfenidone. The method can also further compriserecrystallizing the purified pirfenidone by dissolving at least aportion of the purified pirfenidone in an acidic aqueous solution at anelevated temperature to form a pirfenidone solution; adding a basicsolution to the pirfenidone solution until the pH is at least about 11;and cooling the basic pirfenidone solution to a temperature below about20° C. to form recrystallized pirfenidone. In some cases, the elevatedtemperature is at least about 40° C. In various cases, the acidicaqueous solution comprises hydrochloric acid. In some cases, the basicsolution comprises sodium hydroxide. In various cases, the basicpirfenidone solution is cooled to a temperature below about 10° C. Insome cases, the purifying of the pirfenidone is performed in the absenceof ethyl acetate and butanol. In a specific case, the pirfenidoneprepared by the methods disclosed herein has a purity of at least 98% byweight or molar ratio and is essentially free of or free of ethylacetate and butanol, where essentially free of describes a product whereneither ethyl acetate nor butanol is intentionally added during thesynthetic processes, as described herein. A pirfenidone compositionessentially free of ethyl acetate and/or butanol can permit the presenceof trace amounts of ethyl acetate and/or butanol which are carry-overimpurities, e.g. present in the reagents or starting materials used in asynthetic process such as one described herein. The pirfenidone preparedcan have a purity of at least 99%, and more preferably, at least 99.9%by weight or molar ratio.

In another aspect, disclosed herein is pirfenidone having less thanabout 0.1% by weight or molar ratio of a di(5-methyl-2-pyridone)benzeneimpurity, and preferably less than about 0.05% by weight or molar ratioof a di(5-methyl-2-pyridone)benzene impurity.

In yet another aspect, disclosed herein is pirfenidone having less thanabout 0.1% by weight or molar ratio of an impurity which elutes at arelative retention time of about 1.95 compared to the retention time ofpirfenidone, when analyzed by liquid chromatography. Preferably, thepirfenidone has less than about 0.05% by weight or molar ratio of theimpurity with the relative retention time of 1.95.

In still another aspect, disclosed herein is pirfenidone having lessthan about 0.1% by weight or molar ratio of an impurity which elutes ata relative retention time of about 1.24 compared to the retention timeof pirfenidone, when analyzed by liquid chromatography. Preferably, thepirfenidone has less than about 0.05% by weight or molar ratio of theimpurity with the relative retention time of 1.24.

In another aspect, pharmaceutical compositions comprising pirfenidone asdisclosed herein and a pharmaceutically acceptable excipient aredescribed.

DETAILED DESCRIPTION

Disclosed herein is an improved process for preparing pirfenidone. Theprocess involves using a cuprous oxide catalyst to couple5-methyl-2-pyridone and bromobenzene in an organic solvent. Withoutintending to be limited by any particular theory, it is believed thatthe purity of the bromobenzene is important, as amounts of adibromobenzene impurity in the bromobenzene can lead to dimer-typebyproducts, which can complicate the purification of the resultingpirfenidone. These dimer-type byproducts cannot be in a product intendedas to be marketed as an active pharmaceutical ingredient (API), and theyare difficult to remove from the intended pirfenidone product. Thus, thebromobenzene used in the disclosed processes preferably have an amountof dibromobenzene of less than about 0.15% by weight or molar ratio, andmore preferably less than about 0.1% by weight or molar ratio or lessthan 0.05% by weight or molar ratio. The synthesis of pirfenidone isshown in Scheme 1, below.

As used throughout this disclosure, impurities and purity of compoundsare reported as a percentage (%). Unless indicated otherwise forspecific cases, this percentage can be assessed based upon the weight ofthe sample or composition (e.g., a wt %), or based upon a molar ratio.Molar ratios (e.g., molar percentages) can be measured using thesechromatographic techniques, such as high pressure/high performanceliquid chromatography (HPLC), gas chromatography (GC), or capillaryelectrophoresis (CE). Molar ratios are molecular ratios of the specifiedcompound to the total compounds present.

The bromobenzene preferably is pure monobromobenzene. The bromobenzenepreferably is free of 1,4-dibromobenzene. The bromobenzene preferably isfree of all dibromobenzenes (i.e., 1,2-dibromobenzene,1,3-dibromobenzene, and 1,4-dibromobenzene). The bromobenzene preferablyis free of tribromobenzenes (i.e., 1,2,3-tribromobenzene,1,2,4-tribromobenzene, and 1,3,5-tribromobenzene). The bromobenzenepreferably is free of tetrabromobenzenes (i.e.,1,2,3,4-tetrabromobenzene, 1,2,3,5-tetrachlorobenzene, and1,2,4,5-tetrabromobenzene). The bromobenzene preferably is free ofpentabromobenzene and hexabromobenzene.

The organic solvent of the coupling reaction can be any compatibleorganic solvent, such as an aprotic polar solvent. Non-limiting examplesinclude tetrahydrofuran, diethyl ether, dimethyl formamide,dimethylsulfoxide, dichloromethane, dimethylsulfoxide, sulfolane, andmixtures thereof. In a specific preferred embodiment, the organicsolvent comprises dimethyl formamide. Choice of the appropriate solventcan depend upon the temperature at which the reaction is run. A solventhaving a boiling point above or around that of the reaction temperatureis preferred.

The reaction can be performed at elevated temperatures. An elevatedtemperature is any temperature above room temperature (about 25° C.),and can be at least about 50° C., at least about 70° C., at least about75° C., at least about 80° C., at least about 85° C.., at least about90° C., at least about 95° C., at least about 100° C., at least about105° C., at least about 110° C., at least about 115° C., at least about120° C., at least about 125° C., at least about at least about 130° C.,or at least about 135° C., for example.

The reaction can be performed in the presence of a base. In some cases,the base can be an inorganic base. Inorganic bases include, but are notlimited to, lithium hydroxide, potassium hydroxide, sodium hydroxide,sodium carbonate, potassium carbonate, sodium bicarbonate, potassiumbicarbonate, and mixtures thereof. In one embodiment, the base comprisespotassium carbonate.

Upon formation of the pirfenidone from the coupling reaction, thepirfenidone can optionally be washed with a saline solution. Thiswashing step can remove salts used or formed during the couplingreaction. A saline solution can be a sodium chloride solution, forexample a saturated brine solution. A high concentration sodium chloridesolution provides low yield loss of pirfenidone in the aqueous layer,but a low concentration sodium chloride solution provides bettercompatibility with dimethyl formamide. Thus, an optimal sodium chloridesolution concentration is high enough to minimize loss of pirfenidone inthe aqueous layer, but low enough to allow a maximum amount of dimethylformamide in the aqueous layer. Thus, in some embodiments, the sodiumchloride solution is in a range of about 10 wt % to about 20wt % sodiumchloride, based on the weight of the solution.

The pirfenidone can additionally or alternatively be extracted with anorganic solvent to remove impurities, such as residual organic solventfrom the coupling reaction (e.g., dimethyl formamide). Examples of anextracting organic solvent include, but are not limited to, toluene,diethyl ether, tetrahydrofuran, methylene chloride, and mixturesthereof. In a specific embodiment, the pirfenidone is extracted withtoluene. Extraction with toluene can allow for residual dimethylformamide to remain in the aqueous layer.

The pirfenidone can be precipitated to form a more purified form ofpirfenidone. Crude pirfenidone can be dissolved in a minimum amount oftoluene and heptanes and heated to, e.g., about 50° C. to about 100° C.The solution is slowly cooled to about −5° C. to about 5° C. to allowprecipitation of the pirfenidone. The resulting solid pirfenidoneprecipitate can be collected via filtration and dried.

The pirfenidone can additionally or alternatively be crystallized toform a more purified pirfenidone. For crystallization, the pirfenidonecan be dissolved or partially dissolved in an acidic solution at anelevated temperature, such as at least about 35° C., at least about 40°C., or about 40° C. to about 50° C. The acidic solution can comprise anycompatible inorganic or organic acid. The acidic solution preferablycomprises an inorganic acid. Non-limiting examples of contemplatedinorganic acids include sulfuric acid, hydrochloric acid, hydrobromicacid, nitric acid, phosphoric acid, and mixtures thereof. In a specificembodiment, the acidic solution comprises hydrochloric acid.

The resulting acidic pirfenidone solution can then be treated withaddition of a basic solution until the pH of the pirfenidone solution isat least about 11. The basic solution can comprise any compatibleinorganic or organic base. The basic solution is preferably an inorganicbase. Non-limiting examples of contemplated inorganic bases includelithium hydroxide, potassium hydroxide, sodium hydroxide, sodiumcarbonate, potassium carbonate, sodium bicarbonate, potassiumbicarbonate, and mixtures thereof. In a specific embodiment, the basicsolution comprises sodium hydroxide.

The basic pirfenidone solution can then be cooled slowly to less thanabout 10° C., or about 0° C. to about 9° C. The resulting crystallizedpirfenidone can then be collected via filtration and dried.

For pirfenidone used in clinical trials and as an API, it is importantthat the trace solvent levels be minimized, for example for regulatoryrequirements. Thus, in one aspect, the pirfenidone is essentially freeof or free of ethyl acetate or butanol, for example from having beenprepared without the use of ethyl acetate and/or butanol in any step. Insome cases, the pirfenidone has less than about 30 ppm toluene,heptanes, or both, and preferably has less than about 20 ppm toluene,heptanes, or both. The prepared pirfenidone has a purity of at least 98%by weight or molar ratio, and can have a purity of preferably at least99% by weight or molar ratio or at least 99.5% by weight or molar ratioor at least 99.6% by weight or molar ratio, at least 99.7% by weight ormolar ratio, at least 99.8% by weight or molar ratio, or at least 99.9%by weight or molar ratio.

Pirfenidone according to the disclosure herein, for example preparedusing a method disclosed herein, can additionally or alternatively haveless than about 0.1% by weight or molar ratio, less than about 0.05% byweight or molar ratio, less than about 0.04% by weight or molar ratio,less than about 0.03% by weight or molar ratio, less than about 0.02% byweight or molar ratio, or less than about 0.01% by weight or molar ratioof a di(5-methyl-2-pyridinone)benzene impurity. Examples of suchdi(5-methyl-2-pyridinone)benzene impurities include one or more of

The pirfenidone can additionally or alternatively have less than about0.1% by weight or molar ratio, less than about 0.05% by weight or molarratio, less than about 0.04% by weight or molar ratio, less than about0.03% by weight or molar ratio, less than about 0.02% by weight or molarratio, or less than about 0.01% by weight or molar ratio of an impuritythat has a relative retention time (RRT) of about 1.95 compared to theretention time of pirfenidone, when analyzed by liquid chromatography.The pirfenidone can additionally or alternatively have less than about0.1% by weight or molar ratio, less than about 0.05% by weight or molarratio, less than about 0.04% by weight or molar ratio, less than about0.03% by weight or molar ratio, less than about 0.02% by weight or molarratio, or less than about 0.01% by weight or molar ratio of an impuritythat has a relative retention time (RRT) of about 1.24 compared to theretention time of pirfenidone, when analyzed by liquid chromatography.

An exemplary method for liquid chromatography (LC) analysis ofpirfenidone is using a Hewlett-Packard 11000 Liquid Chromatograph,equipped with a UV detector operating at 220 nm and 310 nm, and a ZORBAXSB-Aq C-18, 5.0 μm, 250 mm×4.6 mm column. The mobile phases are MobilePhase A (MPA) (200 μL phosphoric acid in 1000 mL water) and Mobile PhaseB (MPB) (acetonitrile), which are pumped through the column at a flowrate of 1.0 mL/min and column temperature of 35° C. The mixture of MPAand MPB was a gradient profile over the course of the 25 minute run, asfollows:

Time (Minutes) % MPA % MPB 0 80 20 20 10 90 21 80 20 25 80 20

Pharmaceutical Compositions

While it is possible for the pirfenidone described herein to beadministered alone, it may be preferable to formulate pirfenidone aspharmaceutical compositions. In particular, the pharmaceuticalcompositions can be useful for treating or preventing inflammatoryconditions, e.g., conditions associated with p38 activity or cytokineactivity or any combination thereof. A pharmaceutical composition is anycomposition that may be administered in vitro or in vivo or both to asubject in order to treat or ameliorate a condition. In a preferredembodiment, a pharmaceutical composition may be administered in vivo. Asubject may include one or more cells or tissues, or organisms. Apreferred subject is a mammal. A mammal includes any mammal, such as byway of non-limiting example, cattle, pigs, sheep, goats, horses, camels,buffalo, cats, dogs, rats, mice, and humans. A highly preferred subjectmammal is a human.

In an embodiment, the pharmaceutical compositions may be formulated withpharmaceutically acceptable excipients such as carriers, solvents,stabilizers, adjuvants, diluents, etc., depending upon the particularmode of administration and dosage form. The pharmaceutical compositionsshould generally be formulated to achieve a physiologically compatiblepH, and may range from a pH of about 3 to a pH of about 11, preferablyabout pH 3 to about pH 7, depending on the formulation and route ofadministration. In alternative embodiments, it may be preferred that thepH is adjusted to a range from about pH 5.0 to about pH 8. Moreparticularly, the pharmaceutical compositions may comprise atherapeutically or prophylactically effective amount of at least onecompound as described herein, together with one or more pharmaceuticallyacceptable excipients. Optionally, the pharmaceutical compositions mayinclude a second active ingredient useful in the treatment or preventionof bacterial infection (e.g., a preservative, such as anti-bacterial oranti-microbial agents).

Formulations, e.g., for parenteral or oral administration, are mosttypically solids, liquid solutions, emulsions or suspensions, whileinhalable formulations for pulmonary administration are generallyliquids or powders, with powder formulations being generally preferred.A preferred pharmaceutical composition may also be formulated as alyophilized solid that is reconstituted with a physiologicallycompatible solvent prior to administration. Alternative pharmaceuticalcompositions may be formulated as syrups, creams, ointments, tablets,and the like.

The term “pharmaceutically acceptable excipient” refers to an excipientfor administration of a pharmaceutical agent, such as the compoundsdescribed herein. The term refers to any pharmaceutical excipient thatmay be administered without undue toxicity.

Pharmaceutically acceptable excipients are determined in part by theparticular composition being administered, as well as by the particularmethod used to administer the composition. Accordingly, there exists awide variety of suitable formulations of pharmaceutical compositions(see, e.g., Remington's Pharmaceutical Sciences).

Suitable excipients may be carrier molecules that include large, slowlymetabolized macromolecules such as proteins, polysaccharides, polylacticacids, polyglycolic acids, polymeric amino acids, amino acid copolymers,and inactive virus particles. Other exemplary excipients includeantioxidants (e.g., ascorbic acid), chelating agents (e.g., EDTA),carbohydrates (e.g., dextrin, hydroxyalkylcellulose, and/orhydroxyalkylmethylcellulose), stearic acid, liquids (e.g., oils, water,saline, glycerol and/or ethanol) wetting or emulsifying agents, pHbuffering substances, and the like. Liposomes are also included withinthe definition of pharmaceutically acceptable excipients.

The pharmaceutical compositions described herein may be formulated inany form suitable for an intended method of administration. Whenintended for oral use for example, tablets, troches, lozenges, aqueousor oil suspensions, non-aqueous solutions, dispersible powders orgranules (including micronized particles or nanoparticles), emulsions,hard or soft capsules, syrups or elixirs may be prepared. Compositionsintended for oral use may be prepared according to any method known tothe art for the manufacture of pharmaceutical compositions, and suchcompositions may contain one or more agents including sweetening agents,flavoring agents, coloring agents and preserving agents, in order toprovide a palatable preparation.

Pharmaceutically acceptable excipients particularly suitable for use inconjunction with tablets include, for example, inert diluents, such ascelluloses, calcium or sodium carbonate, lactose, calcium or sodiumphosphate; disintegrating agents, such as cross-linked povidone, maizestarch, or alginic acid; binding agents, such as povidone, starch,gelatin or acacia; and lubricating agents, such as magnesium stearate,stearic acid or talc.

Tablets may be uncoated or may be coated by known techniques includingmicroencapsulation to delay disintegration and adsorption in thegastrointestinal tract and thereby provide a sustained action over alonger period. For example, a time delay material such as glycerylmonostearate or glyceryl distearate alone or with a wax may be employedas a coating or as a matrix.

Formulations for oral use may be also presented as hard gelatin capsuleswherein the active ingredient is mixed with an inert solid diluent, forexample celluloses, lactose, calcium phosphate or kaolin, or as softgelatin capsules wherein the active ingredient is mixed with non-aqueousor oil medium, such as glycerin, propylene glycol, polyethylene glycol,peanut oil, liquid paraffin or olive oil.

In another embodiment, pharmaceutical compositions may be formulated assuspensions comprising a compound of the embodiments in admixture withat least one pharmaceutically acceptable excipient suitable for themanufacture of a suspension.

In yet another embodiment, pharmaceutical compositions may be formulatedas dispersible powders and granules suitable for preparation of asuspension by the addition of suitable excipients.

Excipients suitable for use in connection with suspensions includesuspending agents (e.g., sodium carboxymethylcellulose, methylcellulose,hydroxypropyl methylcellulose, sodium alginate, polyvinylpyrrolidone,gum tragacanth, gum acacia); dispersing or wetting agents (e.g., anaturally occurring phosphatide (e.g., lecithin), a condensation productof an alkylene oxide with a fatty acid (e.g., polyoxyethylene stearate),a condensation product of ethylene oxide with a long chain aliphaticalcohol (e.g., heptadecaethyleneoxycethanol), a condensation product ofethylene oxide with a partial ester derived from a fatty acid and ahexitol anhydride (e.g., polyoxyethylene sorbitan monooleate)); andthickening agents (e.g., carbomer, beeswax, hard paraffin or cetylalcohol). The suspensions may also contain one or more preservatives(e.g., acetic acid, methyl or n-propyl p-hydroxy-benzoate); one or morecoloring agents; one or more flavoring agents; and one or moresweetening agents such as sucrose or saccharin.

The pharmaceutical compositions may also be in the form of oil-in wateremulsions. The oily phase may be a vegetable oil, such as olive oil orarachis oil, a mineral oil, such as liquid paraffin, or a mixture ofthese. Suitable emulsifying agents include naturally-occurring gums,such as gum acacia and gum tragacanth; naturally occurring phosphatides,such as soybean lecithin, esters or partial esters derived from fattyacids; hexitol anhydrides, such as sorbitan monooleate; and condensationproducts of these partial esters with ethylene oxide, such aspolyoxyethylene sorbitan monooleate. The emulsion may also containsweetening and flavoring agents. Syrups and elixirs may be formulatedwith sweetening agents, such as glycerol, sorbitol or sucrose. Suchformulations may also contain a demulcent, a preservative, a flavoringor a coloring agent.

Additionally, the pharmaceutical compositions may be in the form of asterile injectable preparation, such as a sterile injectable aqueousemulsion or oleaginous suspension. This emulsion or suspension may beformulated by a person of ordinary skill in the art using those suitabledispersing or wetting agents and suspending agents, including thosementioned above. The sterile injectable preparation may also be asterile injectable solution or suspension in a non-toxic parenterallyacceptable diluent or solvent, such as a solution in 1,2-propane-diol.

The sterile injectable preparation may also be prepared as a lyophilizedpowder. Among the acceptable vehicles and solvents that may be employedare water, Ringer's solution, and isotonic sodium chloride solution. Inaddition, sterile fixed oils may be employed as a solvent or suspendingmedium. For this purpose any bland fixed oil may be employed includingsynthetic mono- or diglycerides. In addition, fatty acids (e.g., oleicacid) may likewise be used in the preparation of injectables.

To obtain a stable water-soluble dose form of a pharmaceuticalcomposition, a pharmaceutically acceptable salt of a compound describedherein may be dissolved in an aqueous solution of an organic orinorganic acid, such as 0.3 M solution of succinic acid, or morepreferably, citric acid. If a soluble salt form is not available, thecompound may be dissolved in a suitable co-solvent or combination ofco-solvents. Examples of suitable co-solvents include alcohol, propyleneglycol, polyethylene glycol 300, polysorbate 80, glycerin and the likein concentrations ranging from about 0 to about 60% of the total volume.In one embodiment, the active compound is dissolved in DMSO and dilutedwith water.

The pharmaceutical composition may also be in the form of a solution ofa salt form of the active ingredient in an appropriate aqueous vehicle,such as water or isotonic saline or dextrose solution. Also contemplatedare compounds which have been modified by substitutions or additions ofchemical or biochemical moieties which make them more suitable fordelivery (e.g., increase solubility, bioactivity, palatability, decreaseadverse reactions, etc.), for example by esterification, glycosylation,PEGylation, etc.

In a preferred embodiment, pirfenidone described herein may beformulated for oral administration in a lipid-based formulation suitablefor low solubility compounds. Lipid-based formulations can generallyenhance the oral bioavailability of such compounds.

As such, a preferred pharmaceutical composition comprises atherapeutically or prophylactically effective amount of pirfenidonedescribed herein, together with at least one pharmaceutically acceptableexcipient selected from the group consisting of medium chain fatty acidsand propylene glycol esters thereof (e.g., propylene glycol esters ofedible fatty acids, such as caprylic and capric fatty acids) andpharmaceutically acceptable surfactants, such as polyoxyl 40hydrogenated castor oil.

In an alternative preferred embodiment, cyclodextrins may be added asaqueous solubility enhancers. Preferred cyclodextrins includehydroxypropyl, hydroxyethyl, glucosyl, maltosyl and maltotriosylderivatives of α-, β-, and γ-cyclodextrin. A particularly preferredcyclodextrin solubility enhancer is hydroxypropyl-o-cyclodextrin (BPBC),which may be added to any of the above-described compositions to furtherimprove the aqueous solubility characteristics of the compounds of theembodiments. In one embodiment, the composition comprises about 0.1% toabout 20% hydroxypropyl-o-cyclodextrin, more preferably about 1% toabout 15% hydroxypropyl-o-cyclodextrin, and even more preferably fromabout 2.5% to about 10% hydroxypropyl-o-cyclodextrin. The amount ofsolubility enhancer employed will depend on the amount of the compoundof the invention in the composition.

A pharmaceutical composition contains a total amount of the activeingredient(s) sufficient to achieve an intended therapeutic effect whenused with a suitable dosing regimen. More specifically, in someembodiments, the pharmaceutical composition contains a therapeuticallyeffective amount. The total amounts of pirfenidone that may be combinedwith the carrier materials to produce a unitary dosing form will varydepending upon the host treated and the particular mode ofadministration. Preferably, the compositions are formulated in view ofcontemplated dosing regimens so that a dose of between 0.01 to 100 mg/kgbody weight/day of pirfenidone is administered to a patient receivingthe compositions. The total daily dose may be provided in divided dailydoses (e.g. two times per day, three times per day, four times per day),and administered as multiple dosage forms containing sub-therapeuticdosage amounts (e.g., 267 mg per dosage form, administered as threedosage forms taken three times per day for a total of nine dosage formsadministered, e.g. 2403 mg/day pirfenidone).

EXAMPLES

Coupling of Bromobenzene and 5-Methyl-2-pyridone

5-Methyl-2-pyridone (1.0 equivalents), potassium carbonate (1.2equivalents), copper(I) oxide (0.05 equivalents), bromobenzene (1.8equivalents, with a purity of at least 98%, preferably at least 99%, orat least 99.8%), and dimethyl formamide (2.0 volume equivalents) werecharged into an inert reactor. This mixture was heated to 125° C. forabout 18 hours. A sample was collected and analyzed for reactioncompletion. If reaction completion was not satisfactory, the reactionwas maintained at 125° C. for an additional 2 hours. The reactionmixture was then cooled to 25° C. to form a slurry.

The resulting slurry was filtered in a Nutsche filter in order to removesalts. The filter cake was rinsed twice with toluene. The mother liquorand process liquor were collected in Vessel (A). A sodium chloridesolution (15%) was charged into the product solution. The pH wasadjusted to greater than or equal to 11.5 using a 32% sodium hydroxidesolution. The mixture was then agitated. After agitation was stopped,the mixture was allowed to settle for at least 30 minutes to allow thetwo phases to separate. The organic layer was separated and the aqueouslayer was extracted with toluene. The toluene extraction was added tothe organic layer. The combined organics were then washed with a 15%sodium chloride solution and agitated for at least 15 minutes. Theagitation was stopped and the layers were allowed to settle for at least30 minutes. The organic layer was separated from the aqueous layer, andthen carbon treated by flowing it through Zeta Carbon filters for 2hours at 20-25° C. The carbon treated solution was then concentratedunder vacuum to remove all water and much of the toluene.

Heptanes were then added to the concentrated solution, and it was heatedto about 80° C. The solution was slowly cooled to about 0° C. over atleast 7 hours. The pirfenidone precipitated out of the solution, wascollected by filtration and dried, using a Nutsche filter/drier. Thepirfenidone cake was washed twice with a mixture of toluene and heptanes(at 0° C.), then vacuum dried at a temperature of about 42° C. The crudepirfenidone was formed in about 85% yield.

Crystallization of Pirfenidone

Pirfenidone, a 32% hydrochloride solution, and deionized water werecharged in an inert reactor. The mixture was heated to about 45° C.,then a 32% sodium hydroxide solution was titrated into the mixture untilthe pH was at least 11. The temperature of the mixture was maintained atabout 45° C. during the titration. Upon reaching the pH of at least 11,the mixture was then cooled slowly to 5° C., over the course of at least2 hours. The pirfenidone crystallized from this cooled solution and wasisolated in a Nutsche filter/drier. The pirfenidone cake was washedtwice with deionized water (at 5° C.). The pirfenidone was then vacuumdried in the filter/drier at a temperature of about 45° C. Thepirfenidone was also milled through a loop mill in order to reduce theparticle size to less than 150 μm.

The resulting pirfenidone was then analyzed and the only residualsolvents observed were toluene and heptanes at about 10 to 13 ppm. Noethyl acetate or butanol was detected in the pirfenidone. The amount ofbis-conjugate in the purified pirfenidone was 0.03% or less. Allimpurities of the purified pirfenidone were less than about 0.05%.

The foregoing description is given for clearness of understanding only,and no unnecessary limitations should be understood therefrom, asmodifications within the scope of the invention may be apparent to thosehaving ordinary skill in the art.

Throughout the specification, where methods are described as includingsteps, components, or materials, it is contemplated that thecompositions can also consist essentially of, or consist of, anycombination of the recited steps, components or materials, unlessdescribed otherwise.

The practice of a method disclosed herein, and individual steps thereof,can be performed manually and/or with the aid of electronic equipment.Although processes have been described with reference to particularembodiments, a person of ordinary skill in the art will readilyappreciate that other ways of performing the acts associated with themethods may be used. For example, the order of various of the steps maybe changed without departing from the scope or spirit of the method,unless described otherwise. In addition, some of the individual stepscan be combined, omitted, or further subdivided into additional steps.

All patents, publications and references cited herein are hereby fullyincorporated by reference. In case of conflict between the presentdisclosure and incorporated patents, publications and references, thepresent disclosure should control.

What is claimed:
 1. A method of synthesizing pirfenidone comprisingadmixing bromobenzene, 5-methyl-2-pyridone, cuprous oxide, and anorganic solvent under conditions sufficient to form pirfenidone, whereinthe bromobenzene comprises less than about 0.15% by weight or molarratio dibromobenzene.
 2. The method of claim 1, further comprisingwashing the pirfenidone with a saline solution.
 3. The method of claim1, further comprising extracting the pirfenidone from the organicsolvent mixture with an extracting organic solvent.
 4. The method ofclaim 3, wherein the extracting organic solvent comprises toluene. 5.The method of claim 1, further comprising admixing a base with thebromobenzene, 5-methyl-2-pyridone, cuprous oxide, and organic solvent.6. The method of claim 5, wherein the base comprises a carbonate.
 7. Themethod of claim 6, wherein the carbonate comprises potassium carbonate.8. The method of claim 1, wherein the organic solvent comprises dimethylformamide.
 9. The method of claim 1, further comprising crystallizingthe pirfenidone from a solvent mixture comprising heptanes and tolueneto form purified pirfenidone.
 10. The method of claim 9, furthercomprising recrystallizing the purified pirfenidone by dissolving atleast a portion of the purified pirfenidone in an acidic aqueoussolution at an elevated temperature to form a pirfenidone solution;adding a base to the pirfenidone solution until the pH is at least about11 to form a basic pirfenidone solution; and cooling the basicpirfenidone solution to a temperature below about 20° C. to formrecrystallized pirfenidone.
 11. The method of claim 9, comprisingperforming the crystallizing in the absence of ethyl acetate and in theabsence of butanol.
 12. Pirfenidone prepared by a method comprisingadmixing bromobenzene, 5-methyl-2-pyridone, cuprous oxide, and anorganic solvent under conditions sufficient to form pirfenidone; whereinthe bromobenzene comprises less than about 0.15% by weight or molarratio dibromobenzene.
 13. The pirfenidone of claim 12, wherein themethod further comprises crystallizing the pirfenidone from a solventmixture comprising heptanes and toluene to form purified pirfenidone.14. The pirfenidone of claim 13, wherein the method further comprisesrecrystallizing the purified pirfenidone by dissolving at least aportion of the purified pirfenidone in an acidic aqueous solution at anelevated temperature to form a pirfenidone solution; adding a base tothe pirfenidone solution until the pH is at least about 11 for form abasic pirfenidone solution; and cooling the basic pirfenidone solutionto a temperature below about 20° C. to form recrystallized pirfenidone,wherein the recrystallizing is done in the absence of ethyl acetate andin the absence of butanol.
 15. The recrystallized pirfenidone of claim12, having a purity of at least 98% by weight or molar ratio and beingessentially free of ethyl acetate and essentially free of butanol. 16.Pirfenidone having less than about 0.1% by weight or molar ratio of adi(5-methyl-2-pyridinone)benzene impurity.
 17. The pirfenidone of claim16, having less than about 0.05% by weight or molar ratio of adi(5-methyl-2-pyridone)benzene impurity.
 18. The pirfenidone of claim16, having a purity of at least 98% by weight or molar ratio and beingessentially free of ethyl acetate and essentially free of butanol.